Lumateperone

Mechanism of Action

Lumateperone's mechanism of action involves simultaneous modulation of dopaminergic, serotonergic, and glutamatergic neurotransmission.[12][5] Its dopaminergic actions involve pre-synaptic partial agonist and post-synaptic antagonist activity at dopamine D2 receptors.[13] This dual action at the dopamine D2 receptor is unique to lumateperone compared to other antipsychotics. Furthermore, It acts as a dopamine phosphoprotein modulator (DPPM).[13] Lumateperone is also a potent 5-HT2A receptor antagonist, with an affinity that is 60x greater than its affinity to D2 receptors.[2] Finally, lumateperone is the first antipsychotic to exhibit glutamatergic activity, augmenting the activity of NMDA and AMPA receptors.[3][14] 

At dopamine receptors, lumateperone's activity is unique through its activity at D2 receptors compared to first-generation and other recently introduced second-generation antipsychotics.

First-generation antipsychotics block D2 receptors both pre-and post-synaptically. Pre-synaptic inhibition of D2 receptors results in positive feedback and a subsequent increase of dopamine in the synaptic cleft. Only post-synaptic receptor blockade is sufficient in this context. Other agents that are second-generation antipsychotics, such as aripiprazole and brexipiprazole, are D2 receptor partial agonists and allow low dopamine D2 receptor neurotransmission. In both cases, there are unwanted increases in dopaminergic activity and, more importantly, the requirement for higher D2 receptor occupancy. Specifically, they are known to require a 60-80% occupancy of D2 receptors to achieve clinical efficacy in reducing symptoms of schizophrenia. This is thought to result in a higher risk of extrapyramidal side effects.[13]

 In contrast, lumateperone's pre-synaptic partial agonist activity prevents positive feedback at D2 receptors while simultaneously blocking dopaminergic neurotransmission at the post-synaptic D2 receptor. This dual action at D2 receptors prevents an increase in dopamine in the synaptic cleft while simultaneously blocking post-synaptic D2 receptors. It is thought that this is responsible for the fact that lumateperone requires D2 receptor occupancy as low as 40%, an uncommon characteristic in antipsychotics.[13] Both reduced receptor occupancy and its dual action at D2 receptors are thought to contribute to lumateperone's low incidence of extrapyramidal side effects, such as tardive dyskinesia and parkinsonian-like effects. Interestingly, lumateperone appears to be regioselective for mesolimbic brain pathways rather than nigrostriatal pathways.[13][2][3] In addition, post-synaptic antagonism of D2 receptors by lumateperone increases GSK-3 signaling via phosphorylation. GSK3 signaling occurs in D2R-expressing neurons located in the PFC and nucleus accumbens, both of which are implicated in schizophrenia.[3]

Like other second-generation antipsychotics, lumateperone is a 5-HT2A receptor antagonist. The antagonism of 5-HT2A receptors, in addition to the antagonism of D2 receptors, is the defining characteristic of all second-generation antipsychotics. 5-HT2A receptor antagonism, when paired with D2 receptor antagonism, results in a reduced risk of extrapyramidal side effects. The exact mechanism is unknown; however, the 5-HT2A receptor is known to influence dopaminergic activity in the brain.[15]

Importantly, lumateperone exhibits 60x greater affinity for 5-HT2A receptors than D2 receptors. This is thought to be significant in lumateperone's gradient of clinical effects, which provides lumateperone with a potentially more extensive range of clinical use.[3][13][2] At low dosages, lumateperone's effects are mainly sedative and anti-aggressive. The ability of lumateperone to exhibit these effects at low dosages may result from a lack of D2 receptor binding and preferential, potent 5HT2A antagonism at low dosages. In contrast, increasing dosages show increasing D2 receptor binding and occupancy in addition to 5HT2A receptor binding, resulting in antipsychotic efficacy.[3] 

Lumateperone also has other serotonergic modulatory activity acting in addition to being a potent 5-HT2A receptor antagonist. Specifically, it is an inhibitor of the serotonin reuptake transporter, which is the mechanism of action of SSRI antidepressants, resulting in potential antidepressant activity and efficacy against the negative symptoms of schizophrenia (i.e., depression).[3] This may be an essential factor in lumateperone's efficacy in both bipolar depression as well as the negative symptoms associated with schizophrenia.

Lumateperone is unique among other antipsychotics in that it targets the glutamatergic system in the brain. Recently, there has been increasing interest in the role of the glutamatergic system in the neurobiology of schizophrenia. Schizophrenia has been associated with dysregulation of the glutamatergic system in the brain. Unlike dopamine which is restricted to distinct anatomical pathways in the brain, glutamate is the primary excitatory neurotransmitter. As a result, dysregulation of glutamate in the brain may have widespread implications on total brain functioning and is thought to be important to the pathophysiology of schizophrenia.[16]

The NMDA receptors are ionotropic glutamate receptors that are thought to play a role in schizophrenia. Furthermore, it has been proposed that dysregulation of glutamate transmission may be involved in the cognitive deficits associated with negative symptoms of schizophrenia.[11] It is hypothesized that there is a deficiency of NMDA receptors, a type of ionotropic glutamate receptor present in GABA interneurons in patients with schizophrenia. Lumateperone has been found to target NMDA receptors

Lumateperone has been found to augment the activities of NMDA and AMPA receptors in the prefrontal cortex. Although the exact mechanism is unknown, it has been found that this is partly through a D1-receptor-mediated mechanism that results in the phosphorylation of GluN2B subunits of NMDA receptors in the mesolimbic pathways of the brain.[1][17] This correlates with lumateperone's regioselectivity for mesolimbic circuits and lower affinity for nigrostriatal dopamine pathways.[13][2][3] It is thought that this activity may be an important contributor to its effects as an antipsychotic and antidepressant, as NMDA-receptor activity is known to be deficient in schizophrenic patients.[3][14] 

Administration

Lumateperone is administered orally, at the FDA-approved dosage of 42 mg in capsule form, preferably at bedtime. Dosages at 120 mg/day have been shown not to produce any statistically significant improvement in efficacy.[5] It shows rapid absorption following oral administration and has a moderate half-life of 13 to 21 hours. T-max occurs in 3 to 4 hours.[12][3] Lumateperone and its metabolites are entirely excreted in the feces.

Adverse Effects

The adverse effects associated with the administration of lumateperone are mild to moderate.[8] At the FDA-approved dosage of 42mg/day, the most common side effects are somnolence, sedation, fatigue, and constipation.[12] 

In a Phase III clinical trial consisting of 148 participants who received the currently FDA-approved dosage of 42 mg, 17.6% experienced somnolence, 12.7% experienced sedation, and  5.3% experienced fatigue. Overall, 64.7% of this group experienced adverse effects.[12] No more than 5% of participants in either of the lumateperone groups (n=294) experienced extrapyramidal symptoms. Furthermore, there was no statistically significant change in median weight from the placebo. Metabolic endpoints, including changes in triglycerides, blood glucose, and prolactin levels, also did not change significantly from placebo; this appears to be partially attributable to its lack of affinity to off-target receptors, including histaminergic and muscarinic receptors.[12]

Another clinical trial compared lumateperone to a standard-of-care antipsychotic consisting of 302 patients for six weeks. Those who switched to lumateperone from their current antipsychotics experienced statistically significant improvements in parameters measuring LDL-cholesterol, triglycerides, and prolactin levels.[5][8] Although there have only been a limited number of clinical trials so far, evidence points to lumateperone having a reduced risk of adverse effects normally associated with second-generation antipsychotics, although long-term studies are underway to determine the long-term safety and efficacy of lumateperone.[6][18]

Contraindications

Lumateperone undergoes metabolism by the cytochrome P450-3A4 isozyme and interacts with medications that are inhibitors and/or inducers of this isozyme. Therefore, the recommendation is to avoid lumateperone in patients taking a CYP3A4 inducer or moderate to potent CYP3A4 inhibitors. Also, lumateperone is likely to interact with alcohol and other sedatives as it produces sedation, especially at lower dosages.[12] 

Enhancing Healthcare Team Outcomes

The treatment and management of schizophrenia is a multi-dimensional process that involves the coordination and participation of various healthcare practitioners, including psychiatrists, nurses, pharmacists, social workers, and other associated healthcare workers, operating as a coordinated interprofessional team. An alliance between these disciplines is essential to provide the best possible outcome because schizophrenia is a complex disease that necessitates an interprofessional approach to treatment. Because there is no cure for schizophrenia, treatment aims to reduce the symptoms that patients experience. The initial goal is to manage any acute and exacerbated psychotic episodes, where pharmacological treatment plays an important role.[19] The interprofessional paradigm is the best way to optimize therapeutic gains when using lumateperone (and other medications) while minimizing potential adverse events. [Level 5]

Upon proper management of acute symptoms, the other components of schizophrenia, which involve an entire spectrum of psychological, behavioral, and social elements, require attention. Thus, pharmacotherapy is only one aspect of this multi-dimensional paradigm to treat individuals diagnosed with schizophrenia. Treatment of schizophrenia should consider psychological and/or psychosocial therapies and/or other strategies that improve the patient's quality of life, prevent relapse, and manage residual cognitive and behavioral symptoms once the initial symptoms are under control. This approach is especially crucial because pharmacological treatments often cannot address all aspects of the disease.

Therefore, healthcare professionals such as psychologists, social workers, and therapists play an essential role in the treatment process. Current guidelines by the American Psychiatric Association (APA) indicate the need for individualized pharmacological approaches based on the patient's personal preference, clinical response, and adverse effects.[19] The patient and the interprofessional team must work collaboratively in the decision-making process. Without proper management, schizophrenia can be a debilitating and sometimes life-threatening condition in which the patient may potentially harm themselves or others. Therefore, healthcare team members must discuss strategies and communicate effectively to provide the best outcome possible.